The maximum time of effectiveness of many oral dosage forms is only a few hours. In order to maximize patient compliance, it is considered very desirable to reduce the frequency of dosing, thereby reducing the number dosage forms (e.g., tablets, etc.) a patient must take in order to attain effective therapy.
Sustained release formulations for drugs have become increasingly available. This is true especially when the particular drug is relatively soluble. Various formulation techniques have been used for providing a sustained release formulation of soluble drugs. In many such formulations, a drug-containing particle is coated with a coating layer or is dispersed within a continuous matrix such as a polymeric matrix. The coating layer or the matrix Comprises a relatively insoluble material or materials, and the release of the drug is controlled by means of the resistance of the coating layer or matrix against the diffusion of the drug therethrough. The release of the drug from such formulations is driven, e.g., by the gradient of the drug concentration resulting from penetration of, e.g., gastric fluid, by diffusion into the formulation.
The task of preparing controlled release formulations of relatively insoluble drugs has proven to be more difficult, however. Examples of such relatively insoluble drugs include acetaminophen, naproxen and indomethacin.
In part because the bioavailability of relatively insoluble drugs is highly dependent on the particle size of the drug or its specific surface area, much of the prior art directed to the provision of controlled release dosage forms for relatively insoluble drugs involves the use of pellets, beads or spheres having a relatively small particle size.
For example, U.S. Pat. No. 4,840,799 (Appelgren, et al.) is related to the preparation of rapidly disintegrating core granulates of slightly soluble drugs (solubility of &lt;1000 mg/l) wherein the drug in particulate form is coated with a layer of an emulsifier/tensile having the same HLB-value as the solubility of the drug. The product is said to provide high bioavailability via the rapid disintegration and release of the drug at a suitable location along the gastrointestinal tract.
With regard to controlled (slow) release formulations, in U.S. Pat. No. 4,752,470 (Mehta), a controlled release indomethacin formulation is described wherein coated pellets of indomethacin of only one type are described. The pellet is said to release indomethacin in both immediate and sustained release form. The pellet consists of a non-pareil bead which supports indomethacin and a binder agent, which is then coated with a mixture of hydroxypropyl cellulose, ethyl cellulose and a plasticizer. The loaded pellets are preferably composed of 2-10% by weight binder, and about 5-30% by weight indomethacin. The pellets are then coated with 0.5-10% by weight of the mixture of hydroxypropyl cellulose and ethyl cellulose. The ratio of ethyl cellulose to hydroxypropyl cellulose depends upon the desired controlled release characteristics.
U.S. Pat. No. 5,133,974 (Paradissis, et al.) describes an extended release formulation which consists of a mixture of 0-50% immediate release particles containing a drug, an inert substrate and binder coated with talc, and up to 100% of an extended release particle comprising the immediate release particle coated with a dissolution modifying system containing plasticizers and a film forming agent. Optionally, additionally a drug is included in the coating.
On the other hand, U.S. Pat. No. 4,892,741 (Ohm, et al.) describes a coated tablet consisting of a core which contains a dihydropyridine having a low aqueous solubility (e.g., nifedipine, nitrendipine, nimodipine and nisoldipine) in rapid-release form and a coating around the core containing a dihydropyridine in slow-release form. The rapid-release core preferably contains the active compound in amorphous form or in a finely grounded or micronized crystalline form. The granules for the coating of the tablet contain 10-99% of hydrophilic gel-forming polymers together with the drug. The coating is carried out on a press coater.
U.S. Pat. No. 3,184,386 describes tablets having a rapid-release preparation in the outer coating. The core primarily has a function of not allowing the surface of the outer coating containing the drug to become too small for release purposes. However, the core does not contain drug in rapid-release form. Both the central coat and the core are also described in the examples as slow-release forms of highly soluble active compounds. U.S. Pat. No. 3,558,768 also describes coated tablets which contain drug in the slow-release form both in the core and in the coating.
It has been found, that, when attempting to prepare controlled-release tablets of an insoluble drug contained within a controlled release matrix, such formulations suffer from unacceptable batch to batch and dosage unit to dosage unit dissolution variability which would in turn result in such products not being commercially viable.